The overall purpose of this project is to explore the molecular basis for amyloid-induced changes in basal neurotransmission and synaptic plasticity at synapses between pyramidal neurons in the hippocampus, a structure within the temporal lobe particularly critical for memory storage and with remarkable plastic characteristics of the kind that are required for learning and memory. Our approach is to combine the use of in vitro hippocampal slices and neuronal cultures with in vivo animals. This strategy offers the advantage of identifying changes of synaptic transmission in a preparation with intact neuronal circuits (slice), of giving depth to the knowledge of these changes in a more simplified system with the unique possibility of having direct access to both the pre- and the post-synaptic site (cell culture), and finally of determining whether it is possible to re-establish normal learning and memory by counteracting the effects of these changes in an in vivo complex neuronal system (the whole animal). The following aims will be addressed: a) to determine changes of synaptic transmission induced by amyloid-beta, b) to search for potential mechanisms that might alter neurotransmission following amyloid-beta increase, c) to determine if changes of synaptic transmission induced by amyloid-beta involve the nitric oxide (NO)/soluble guanylyl-cyclase (sGC)/cGMP/cGMPdependent- protein kinase (cGK)/CREB pathway, d) to determine if the disruption of learning and memory occurring in APP/PS1 mice is rescued by drugs acting through the NO/sGC/cGMP/cGK/CREB pathway. On the completion of these studies we will clarify whether amyloid-beta causes synaptic dysfunction through pre- and/or post-synaptic mechanisms. We will also identify a new signaling pathway inactivated by amyloid peptides during synaptic plasticity and learning. Findings derived from these studies will contribute to the design of researchers and therapies for Alzheimer's Disease and a host of other neurodegenerative disorders with staggering social, economic and personal costs to the sufferers, their families and all of society.